Protein synthesis inhibitors impair the formation of new memories, block analogs of memory such as long-term potentiation and depression, and block other instances of neural change including drug tolerance and extinction. These findings provide the foundation for the view that memory and other durable changes in the brain are formed by processes dependent on de novo protein synthesis. However, amnesias produced by protein synthesis inhibitors may be mediated by consequences of inhibition of protein synthesis other than loss of new proteins needed for memory formation. Using in vivo microdialysis in combination with local brain injections, we recently obtained findings showing extraordinary changes in neurotransmitter release after injections of the protein synthesis inhibitor, anisomycin, into the amygdala. Release of norepinephrine, dopamine and serotonin at the site of injection soared initially before falling well below baseline values during the subsequent hours. In addition, anisomycin-induced amnesia was attenuated by co-administration of drugs aimed at blocking the consequences of neurotransmitter release soon after anisomycin injection or at reversing the consequences of later depressed release. These findings suggest that neurotransmitter responses to the drug, rather than protein synthesis per se, may account for anisomycin-induced impairments in memory. The results thereby raise significant questions about some of the fundamental support for many theories about the molecular bases of memory. This proposal will test the generality of the recent findings by: (1) examining the effects on release of biogenic amines of intra- amygdala injections of cycloheximide, which inhibits protein synthesis by a mechanism different that of anisomycin, and (2) examining the effects on release of biogenic amines of protein synthesis inhibitors administered directly to the hippocampus. The results of these experiments will extend the recent findings obtained with one inhibitor (anisomycin) and one brain region (amygdala) to determine whether protein synthesis inhibition more generally impairs memory by altering neurotransmitter actions. These findings may place the mechanisms underlying the effects of protein synthesis inhibitors on memory within the context of modulation of memory by monoamines and other neurotransmitters. A central tenet of contemporary models of memory and neural plasticity is that the underlying brain changes pass through two major phases, an early protein synthesis- independent phase and a later protein synthesis-dependent phase. These views have become fundamental and rarely questioned properties of the molecular basis of memory formation. These views have also been applied to the mechanisms underlying a wide range of other forms of brain changes, including drug abuse and relapse, epilepsy, and organization of motor cortex and other brain areas during development and during reorganization after stroke. In each of these contexts, the basic evidence is that protein synthesis inhibitors block enduring neural changes - i.e. memory, drug relapse, epilepsy, or motor cortex organization - by blocking mechanisms of change that require protein synthesis. Our recent findings call into question the interpretation of data obtained with the most commonly used protein synthesis inhibitor, anisomycin, by provided clear evidence that the effects on memory are mediated by neurotransmitter responses to the insult of protein synthesis inhibition. The research proposed here examines key properties regarding the generality of these findings, across brain areas and across drugs that interfere with protein synthesis. If these findings are indeed general, will require a reconsideration of basic molecular mechanisms underlying many forms of neural plasticity, with direct applications of the findings to neural processes of memory, development, drug abuse, and epilepsy among other functions in brain and cognition. [unreadable] [unreadable] [unreadable]